A novel approach to the treatment of schizophrenia involving glutamatergic neurotransmission and its modulation with simple amino acids is beginning to generate interest among psychiatrists. Not only are more research studies being published in the psychiatric literature but there was an entire workshop on the topic at the most recent meeting of the American Psychiatric Association meeting in Toronto this past May (2006).

CONVENTIONAL THEORIES

Traditionally, schizophrenia has been thought to be a disease involving the neurotransmitter dopamine. In the early 1950s, it was found that chlorpromazine which was originally developed as an anti-nausea treatment also helped improve psychotic symptoms. It helped relieve the positive symptoms of psychosis by blocking dopamine in the brain. Neurons in the brain are not connected to each other but are separated by gaps called synapses. Chemical messengers are released by one neuron and are received by specialized receptors on the ends of the opposite neuron. The messages they convey are then transmitted down the neuron.

Dopamine is one such chemical messenger or neurotransmitter. Chlorpromazine acts as an antagonist to dopamine and blocks the dopamine receptors on the ends of neurons. This prevents dopamine from binding to the receptor and sending its message down the neuron. As chlorpromazine helped reduce psychotic symptoms, it was thus believed that schizophrenia was a disease of either too much dopamine or too many dopamine receptors. This theory was further supported by the observations that amphetamines and LSD produce hallucinations similar to schizophrenia. These drugs are dopamine agonists that mean that they mimic the action of dopamine in the brain. Their presence has the same effect as increasing the amount of dopamine.

These early antipsychotics that only influenced the dopamine system tend to be only effective for the treatment of the positive symptoms of schizophrenia and are not effective for the negative ones. This led to the consideration that other neurotransmitters might also be involved with the disease. The newer atypical antipsychotics that have been developed in recent years, therefore, influence not only the dopaminergic systems but also effect serotonin - another of the neurotransmitters in the brain. These newer drugs reduce dopamine activity in some parts of the brain and increase serotonin activity in other parts.

THE PCP THEORY

Over the past few years, attention has been focused on the glutamatergic system involving agents that block N-methyl-d-aspartate or NMDA. Glutamic acid is the major excitatory neurotransmitter in the brain involving 40% of all synapses. Two street drugs, PCP (angel dust) and ketamine (the date rape drug) are known to cause behavior that closely resembles that of schizophrenia. These drugs block the N MDA receptors. In fact, the psychosis induced by both PCP and ketamine very closely resemble schizophrenia because they not only produce positive symptoms but also the negative symptoms and cognitive deficits that are so resistant to treatment in schizophrenia.

Post mortem evaluations of the brains of people with schizophrenia have shown that they have fewer NMDA receptors than people who do not have the disease. Both glycine and d-serine (NMDA agonists) have been found to be decreased in both the blood and cerebrospinal fluid of people with schizophrenia compared to controls. This has all led to the hypothesis that people with schizophrenia have too little NMDA and that is one cause of some of the symptoms of the disease – particularly the negative symptoms and the cognitive deficits.

This knowledge has lead to a number of investigations evaluating the effect of various agents that will increase the amount of NMDA in the brains of those with schizophrenia

NMDA AGONISTS

Glycine is known to act as an agonist for NMDA. That is it mimics NMDA. Glycine is an amino acid that is found in the protein of all living things. The normal human diet results in an intake of about 2 grams of glycine daily. It is believed that supplementing with glycine may not only have antispastic activity but it may also have antipsychotic activity along with anti-oxidant and anti-inflammatory properties.

A number of small, randomized control trials have been done looking at the effect of adding glycine to atypical antipsychotics and the impact that would have on symptoms. In January 2005, a team of Finnish researchers published a meta-analysis in Schizophrenia Research (Vol 72, Issues 2-3, pages 225-234). A meta-analysis combines the results from all studies and re-analyzes the data. This has the advantage of increasing the sample size by combining studies.

In this case, there were 18 short-term trials included in the meta-analysis involving 343 patients who were given various NMDA agonist compounds in addition to their antipsychotics. The study found that both glycine and D-serine (another amino acid synthesized in the body from glycine) were effective in reducing negative symptoms but that the magnitude of the effect was small.

Two other recent trials were published in Biological Psychiatry in 2004 and 2005. The first by Uriel Heresco-Levy and colleagues is entitled “High dose Glycine Added to Olanzapine and Risperidone for the Treatment of Schizophrenia” (vol 55 pages 165-171) Seventeen patients on either olanzapine or risperidone were given 8 g/day of glycine in addition to their regular medications for a 6-week period. Patients were then switched. If they were getting placebo during the first six weeks, they received glycine in the second phase and vice versa. The trial was blind so that neither the researchers nor the patients knew what was being taken.

It was found that glycine was well tolerated by the patients and that there was a significant reduction in negative symptoms. The size of the sample, however, was small and the length of the study was short but the researchers did conclude that the efficacy of risperidone and olanzapine might be augmented using high dose adjuvant glycine treatment.

The researchers found that there were significant improvements in negative, positive, cognitive and depression symptoms. While gylycine and D-serine both act as NMDA agonists, there are differences between them. Glycine passes the blood brain barrier with greater difficulty and thus more of it must be taken in order for it to reach the brain than D-serine. However, D-serine has been found to cause kidney damage in rats and, until its safety has been determined, it is not approved for clinical use in the U.S.

Some rather disappointing results were obtained with the as yet unpublished multi-center study called Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST). This study (the largest to date) was designed to evaluate the efficacy of either glycine or d-cycloserine (a partial NMDA agonist) as an add-on to antipsychotics other than clozapine. The study involved 135 subjects for a 16-week period.

While no significant effects were found for either study compound, Dr. Daniel Javitt told the workshop at the APA meeting that the findings were “not all doom and gloom”. There were some interesting subgroup findings. A subgroup analysis found that there was a significant reduction in symptoms amongst in-patients treated with glycine. This is consistent with earlier studies that all used in-patients rather than outpatients.

Why this was the case is not known.

Another possible problem was that the dosing was lower in this study. Glycine should be given at the rate of 0.8 g per kilogram of body weight but in this study all patients received 60 g per day of glycine. Also, in the earlier studies, the serum levels of glycine reached 1000 nmol/ml but in this study it only reached 600 nmol/ml. Clearly, more studies on glycine dosing need to be done.

A more positive pilot study on patients in the prodromal phase of schizophrenia who were given glycine was sufficiently positive that it was halted early and a randomized placebo controlled trial begun.

According to Scott W. Woods of the PRIME early intervention clinic at Yale University, schizophrenia develops from premorbid to prodromal to fully psychotic. There is, he said, likely a progression of pathophysiologic mechanisms involved in the disease. Treatment targeting mechanisms operating during the prodromal phase could prevent progression of the illness and the development of full psychosis.

The study he described that was conducted at Yale looked at the role that glycine might have in preventing progression of the disease in patients who exhibited prodromal symptoms. Glycine occurs naturally in the body and is available as a supplement. Consequently, 10 subjects were selected and treated with 0.8 g/kg of glycine for 8 weeks. The glycine proved to be very effective at reducing symptoms and demonstrated better results than were found with a similar study using olanzapine. Many of the patients met the criteria for full remission after 8 weeks of treatment.

As a result of these positive findings, the pilot study was halted and a 12 week randomized trial is now recruiting subjects. The caveat for the pilot study is that it was an open label trial without placebo and more realistic findings will be obtained from the placebo study.

NMDA ANTAGONISTS

The studies described above are all using NMDA agonists but there is another possible method that might be successful at increasing levels of NMDA. That is the use of an NMDA antagonist that would work like the current SSRI anti-depressants. The current class of anti-depressants work by preventing serotonin from being degraded after it has done its job. When serotonin, or any other neurotransmitter, delivers its message across the synapse and reaches the receptor on the next neuron, it is eliminated or neutralized. The SSRIs prevent that from happening thus enabling more serotonin to remain in the brain. They are serotinin antagonists.

Dr. Tsai and his colleagues completed their double blind randomized control trial on 36 patients with schizophrenia who were being treated with antipsychotics. Patients were assigned to receive either 2 g/day of sarcosine or placebo. sarcosine outperformed placebo. There was a 17% reduction in positive symptoms with sarcosine compared to placebo, a 14% reduction in the negative symptoms and a 13% improvement in cognition compared to placebo. There were no differences in side effects.

Another small trial comparing sarcosine to D-serine as add-on treatments was also positive (Arch Gen Psychiatry, vol 62, Nov 2005, 1196-1204). In this study, Dr. Tsai and his colleagues randomized 65 subjects toeither risperidone plus placebo, risperidone plus D-serine or risperidone plus sarcosine. The sarcosine group had greater reduction on the PANSS total score than either placebo or D-serine. On the SANS test, sarcosine was also superior to the two other study arms.

Dr. Tsai who presented his data at another workshop at the APA and who was interviewed for this article stated that “this study indicates that sarcosine….may be more efficacious than NMDA glycine site agonists for adjuvant treatment of schizophrenia at least in the acute phase”.

AMPAKINES

Ampas are subtypes of receptors that recognize glutamate and are involved in a process known as long-term potentiation, or LTP that is involved with memory. It is believed that AMPA receptor activity modulated with AMPAKINE drugs may provide a new and highly affective approach to treating a number of central nervous system disorders such as Alzheimer’s disease and schizophrenia.

This is the research direction that Dr. Donald C Goff of Harvard is taking. He told the workshop that ampakines are able to open the gated NMDA channels in the brain by depolarization. That is, changing the membrane cells electrically to become more positive. This has the effect of removing the magnesium blockade, opens the channel and allows more NMDA to be present.

There are a number of different ampakines but he conducted his research on a compound called CX516 that he admitted was a low potency ampakine with a very short half-life.

In this study, 105 patients were randomized to continue to receive their usual antipsychotic with the add on of either a placebo or 300 mg of CX516 3 times/day for 4 weeks. While the analysis showed no difference in the composite cognitive score, there were interesting differences between those taking clozapine and those on other atypical antipsychotics. Those on clozapone and the ampakine had a worsening of their symptoms that approached statistical significance. The patients on the ampakine and other atypicals did show an improvement in cognitive symptoms that approached significance.

Dr. Goff suggested that the poor results may have been the result of using an ampakine that is not very potent and that more potent compounds may prove to be beneficial. He also pointed out that the negative results with patients taking clozapine might be caused by the fact that clozapine might also be an NMDA agonist. This possibility has been mentioned by other researchers as clozapine is the only antipsychotic that improves negative symptoms and cognition.

CONCLUSION

From the preliminary studies that are being conducted, this avenue does show considerable promise. However, if anyone does wish to try glycine, it is highly recommended that it only be done in consultation with the doctor and that the glycine used is made to either prescription or pharmaceutical grade standards. Clinical trials have begun with 15 gm per day and the dose is then increased by 15 gm per day every 3 days until a total dose of 60 gm/day has been achieved. This dose is based upon an average weight for the individual of about 150 pounds.

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